Acute acrylonitrile toxicity: studies on the mechanism of the antidotal effect of D- and L-cysteine and their N-acetyl derivatives in the rat.
Thiol-containing antidotes for acute acrylonitrile (AN) toxicity may exert their action by chemically reacting with AN, by replacing critical sulfhydryl groups cyanoethylated by AN, and by detoxifying cyanide produced from AN metabolism. We have evaluated the ability of the optical isomers of cysteine and N-acetylcysteine to act as antidotes against AN toxicity in order to assess the relative importance of each of these three antidotal mechanisms. The toxicity of AN was determined in male Sprague-Dawley rats and compared to the toxicity determined after treatment with 2 mmol/kg of thiol antidote by computing a protective index (median lethal dose with antidote/median lethal dose without antidote). The protective indices of L-cysteine, D-cysteine, N-acetyl-L-cysteine, and N-acetyl-D-cysteine were 2.03, 1.97, 1.76, and 1.25, respectively. Measurements of urinary mercapturates, derived from the non-oxidative pathway of AN metabolism, indicated that none of the antidotes was able to significantly increase the excretion of these metabolites. Blood cyanide generated from the oxidative metabolism of AN and butyronitrile was also determined. All of the antidotes, except N-acetyl-D-cysteine, lowered blood cyanide levels. A comparison of these results with the predicted relative abilities of the enantiomers to participate in each of the three antidotal mechanisms leads to the conclusion that, under these experimental conditions, the best correlation exists with the cyanide detoxification mechanism.
Benz
F W
FW
Department of Pharmacology and Toxicology, University of Louisville, Kentucky 40292.
Nerland
D E
DE
Pierce
W M
WM
Babiuk
C
C
D000111:Acetylcysteine / Q000627:therapeutic use* / Q000652:urine; D000181:Acrylonitrile / Q000493:pharmacokinetics / Q000506:poisoning* / Q000633:toxicity; D000208:Acute Disease; D000818:Animals; D000931:Antidotes; D003545:Cysteine / Q000031:analogs & derivatives* / Q000627:therapeutic use* / Q000652:urine; D004353:Drug Evaluation, Preclinical; D007536:Isomerism; D007928:Lethal Dose 50; D008297:Male; D009570:Nitriles / Q000506:poisoning*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000931:Antidotes; D009570:Nitriles; D003545:Cysteine; D000181:Acrylonitrile; D000111:Acetylcysteine